Graves, Patricia M., Gelband, Hellen, and Garner, Paul (2012) Primaquine for reducing Plasmodium falciparum transmission. Cochrane Database of Systematic Reviews, 9. CD008152. pp. 1-78.

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Abstract

Background: Mosquitoes become infected with malaria when they ingest gametocyte stages of the parasite from the blood of a human host. Plasmodium falciparum gametocytes are sensitive to the drug primaquine (PQ). The World Health Organization (WHO) recommends giving a single dose or short course of PQ alongside primary treatment for people ill with P. falciparum infection to reduce malaria transmission. Gametocytes themselves cause no symptoms, so this intervention does not directly benefit individuals. PQ causes haemolysis in some people with glucose-6-phosphate dehydrogenase (G6PD) deficiency so may not be safe.

Objectives: To assess whether a single dose or short course of PQ added to treatments for malaria caused by P. falciparum infection reduces malaria transmission and is safe.

Search methods: We searched the following databases up to 10 April 2012 for studies: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; metaRegister of Controlled Trials (mRCT) and the WHO trials search portal using 'malaria*', 'falciparum', and 'primaquine' as search terms. In addition, we searched conference proceedings and reference lists of included studies, and we contacted likely researchers and organizations for relevant trials.

Selection criteria: Trials of mass treatment of whole populations (or actively detected fever or malaria cases within such populations) with antimalarial drugs, compared to treatment with the same drug plus PQ; or patients with clinical malaria being treated for malaria at health facilities randomized to short course/single dose PQ versus no PQ.

Data collection and analysis: Two authors (PMG and HG) independently screened all abstracts, applied inclusion criteria, and abstracted data. We sought data on the effect of PQ on malaria transmission intensity, participant infectiousness, the number of participants with gametocytes, and gametocyte density over time. We stratified results by primary treatment drug as this may modify any PQ effect. We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available, and also sought data on haematologic and other adverse effects. We used GRADE guidelines to assess evidence quality, and this is reflected in the wording of the results: high quality ("PQ reduces .... "); moderate quality ("PQ probably reduces ... "); low quality ("PQ may reduce .... "); and very low quality ("we don't know if PQ reduces .... ").

Main results: We included 11 individually randomized trials, with a total of 1776 individuals. The 11 trials included 20 comparisons with partner drugs, which included chloroquine (CQ), sulfadoxine-pyrimethamine (SP), mefloquine (MQ), quinine (QN), artesunate (AS), and a variety of artemisinin combination therapies (ACTs). For G6PD deficiency, studies either did not test (one study), tested and included all (one study), included only G6PD deficient (one study), excluded G6PD deficient (two studies), or made no comment (six studies).

None of the trials we included assessed effects on malaria transmission (incidence, prevalence, or entomological inoculation rate (EIR)) in the trial area.

With non-artemisinin drug regimens, PQ may reduce the infectiousness to mosquitoes of individuals treated, based on one small study with large effects (Risk Ratio (RR) 0.06 on day 8 after treatment, 95% confidence interval (CI) 0 to 0.89; low quality evidence). Participants who received PQ had fewer circulating gametocytes up to day 43 (log(10) AUC relative decrease from 24.3 to 27.1%, one study (two comparisons), moderate quality evidence); and there were 38% fewer people with gametocytes on day 8 (RR 0.62, 95% CI 0.51 to 0.76, four studies (five comparisons), moderate quality evidence). We did not identify any study that looked for effects of the drug on haemolytic anaemia.

With artemisinin-based drug regimens, we do not know if PQ influences infectiousness to mosquitoes, as no study has examined this directly. PQ probably reduces infectiousness, based on reduction in log(10) AUC (relative decrease range from 26.1% to 87.5%, two studies (six comparisons), moderate quality evidence); and reduces by 88% the number of participants with gametocytes on day 8 (RR 0.12, 95% CI 0.08 to 0.20, four studies (eight comparisons), moderate quality evidence).

When used with artemisinin-based regimens, we do not know if PQ results in haemolytic anaemia; one trial reported percent change in mean haemoglobin against baseline, and for the PQ group this indicated a significantly greater drop at day 8 in those given PQ (very low quality evidence). Overall, the safety of PQ used in single dose or short course was poorly evaluated.

Authors' conclusions: We do not know whether PQ added to treatment regimens for patients with P. falciparum infection reduces transmission of malaria. In individual patients, it reduces gametocyte prevalence and density. In practical terms, even if PQ results in large reductions in gametocytes in people being treated for malaria, there is no reliable evidence that this will reduce transmission in a malaria-endemic community, where many people are infected but have no symptoms and are unlikely to be treated. Since PQ is acting as a monotherapy against gametocytes, there is a risk of the parasite developing resistance to the drug. In terms of harms, there is insufficient evidence from trials to know whether the drug can be used safely in this way in populations where G6PD deficiency occurs.

In light of these doubts about safety, and lack of evidence of any benefit in reducing transmission, countries should question whether to continue to use PQ routinely in primary treatment of malaria. Further synthesis of observational data on safety and new trials may help elucidate a role for PQ in malaria elimination, or in situations where most infected individuals are symptomatic and receive treatment.

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